RESUMO
Dehydrogenases are oxidoreductase enzymes that play a variety of fundamental functions in the living organisms and have primary roles in pathogen survival and infection processes as well as in cancer development. We review here a sub-set of NAD-dependent dehydrogenases involved in human diseases and the recent advancements in drug development targeting pathogen-associated NAD-dependent dehydrogenases. We focus also on the molecular aspects of the inhibition process listing the structures of the most relevant molecules targeting this enzyme family. Our aim is to review the most impacting findings regarding the discovery of novel inhibitory compounds targeting the selected NAD-dependent dehydrogenases involved in cancer and infectious diseases.
Assuntos
Doenças Transmissíveis/tratamento farmacológico , Descoberta de Drogas , NAD/química , Neoplasias/tratamento farmacológico , Oxirredutases/metabolismo , Aldeído Oxirredutases/química , Animais , Antimaláricos/uso terapêutico , Antituberculosos/uso terapêutico , Desenho de Fármacos , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Inibinas/química , Isoenzimas/química , Malária/tratamento farmacológico , Tuberculose/tratamento farmacológicoRESUMO
This study sought to examine the functional significance of mitochondrial protein acetylation using a double knockout (DKO) mouse model harboring muscle-specific deficits in acetyl-CoA buffering and lysine deacetylation, due to genetic ablation of carnitine acetyltransferase and Sirtuin 3, respectively. DKO mice are highly susceptible to extreme hyperacetylation of the mitochondrial proteome and develop a more severe form of diet-induced insulin resistance than either single KO mouse line. However, the functional phenotype of hyperacetylated DKO mitochondria is largely normal. Of the >120 measures of respiratory function assayed, the most consistently observed traits of a markedly heightened acetyl-lysine landscape are enhanced oxygen flux in the context of fatty acid fuel and elevated rates of electron leak. In sum, the findings challenge the notion that lysine acetylation causes broad-ranging damage to mitochondrial quality and performance and raise the possibility that acetyl-lysine turnover, rather than acetyl-lysine stoichiometry, modulates redox balance and carbon flux.